The prevalence of obesity is increasing dramatically in western society, especially in the U.S. where 22% of the population have a body mass index greater than 30 kg/m2. As weight is gained, individuals can develop elevated, resting levels of PaCO2 and depressed hypercapnic ventilatory responses (Obesity Hypoventilation Syndrome; OHS). The mechanisms that link obesity and respiratory depression are unclear. The premise of this proposal is that the recently cloned metabolic hormone, leptin, can prevent respiratory depression in obesity. Our findings indicate that obese ob/ob mice, which lack circulating leptin, exhibit the major clinical features of OHS, and that leptin replacement reverses respiratory depression independent of weight. The current application is designed to explore influences of leptin on ventilatory control, and the pathways and factors which modulate its effect. Various transgenic mice and novel techniques are employed to measure ventilation, sleep wake/state and arterial blood gases in chronically instrumented mice. Insights gained from murine experiments will be applied in humans to define the relationship between leptin and ventilation in obesity. Specific Aim l, examines whether leptin can increase the gain of central chemoreceptors, and whether an acute 10% reduction in body fat in obese mice affects ventilatory control. Specific Aim 2 examines whether leptin acts through hypothalamic and peripheral chemoreceptor pathways to alter respiratory control. Specific Aim 3, examines whether leptin is upregulated as a compensatory response to chronic hypoxia. In Specific Aim 4, the mechanistic animal studies will be extended to determine how leptin levels in the CNS relate to PaCO2 in severely obese humans. Finally, the role of gender and sleep/wake state will be explored across Specific Aims 1-4. These studies will enhance understanding of the pathogenesis of respiratory failure in obesity, provide insight into the role of leptin in patients with ventilatory insufficiency of other causes, and offer the possibility of specific therapeutic intervention.